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Title: The investigation of the effects of metformin in thyroid cancer
Author: Kheder, Safar
ISNI:       0000 0004 7226 7919
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment, and some sub-types have poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). Proposed mechanisms include activation of Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway; inhibition of mTOR pathway; reduction in blood glucose and insulin levels by inhibiting hepatic gluconeogenesis and increasing peripheral glucose uptake. OCT1 (organic cation transporter 1) helps in the uptake of Metformin into liver cells. Aims: Explore the anti-cancer effect of Metformin on the growth and proliferation of thyroid cancer cell lines. Methods: The effects of Metformin on thyroid cancer cell lines (FTC-133, K1E7, RO82-W-1, 8305C and TT) and normal thyroid follicular cells (Nthy-ori 3-1) were investigated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay for cell proliferation; clonogenic assay; Fluorescence-activated Cell Sorting (FACS) analysis for apoptosis (using double staining with Annexin V-FITC stained early apoptotic cells and propidium iodide stained late apoptotic cells) and cell cycle (using propidium iodide staining); and H2A.X phosphorylation (?H2AX) assay for DNA repair. Immunocytochemistry was used to investigate OCT1 expression to evaluate the mechanism of action of Metformin. The effects of Thyroid Stimulating Hormone (TSH), insulin and Insulin-like Growth Factor- 1 (IGF-1) on the response to Metformin treatment were also investigated. Affymetrix assay was used for gene expression profiling of cell lines before and after Metformin treatment. Results: Metformin inhibited cell proliferation and colony formation at a minimum concentration of 0.03 mM and increased the percentage of apoptotic cells at concentrations of 0.1 mM and above. Metformin also induced cell cycle arrest in G0/G1 phase at minimum concentration of 0.3 mM. Unlike previous reports, Metformin did not appear to affect response to DNA repair. OCT1 expression was observed in all thyroid cancer cell lines, but no significant difference was observed in the proportion and intensity of OCT1 expression in Metformin treated and non-treated cells. Anti-cancer effects of Metformin (cell proliferation and apoptosis) was amplified in the glucose-free medium compared to glucose-rich medium. Metformin inhibited cell proliferation regardless of the presence of TSH, IGF-1 and insulin in the medium. Metformin modulated the expression of numerous genes and provided clues to the mechanism of action. Conclusion: Metformin suppresses thyroid cancer proliferation in vitro at concentrations within the therapeutic range for diabetic patients. This effect appears to be independent of TSH, insulin, glucose and IGF-1. Further work is needed to determine the molecular mechanisms underlying the observed effects.
Supervisor: Sisley, Karen ; Balasubramanian, Saba ; Hadad, Sirwan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available